title: A comparative study of enol aldehyde formation from betamethasone, dexamethasone, beclomethasone and related compounds under acidic and alkaline conditions.
abstract: Enol aldehydes are one type of key degradation and metabolic intermediates from a group of corticosteroids containing the 1,3-dihydroxyacetone side chain on their D-rings, such as betamethasone, dexamethasone, beclomethasone, and related compounds. The formation of enol aldehydes from these corticosteroids is via acid-catalyzed beta-elimination of water from the side chain, a process known as Mattox rearrangement. It was recently reported by our group that enol aldehydes could also be formed directly from the corresponding 17,21-diesters of these corticosteroids but only under alkaline condition, which was proposed to follow a variation pathway of the original Mattox rearrangement. In this paper, we report the results of a comparative study of enol aldehyde formation from these structurally similar corticosteroids (under the original acidic Mattox condition) and their 17,21-diesters (under the alkaline Mattox variation condition), respectively. In general, enol aldehydes were found to be formed under both conditions; however, the ratios of the E- and Z-isomers of the enol aldehyde were different in each case. The only exception was beclomethasone 17,21-diester under the alkaline condition, where a competing elimination of HCl from the 9,11-positions became predominant. These results can be explained by their structural differences with regard to the Mattox mechanism and its variation pathway. Lastly, solvent effect under acidic condition was studied between an aprotic and a protic solvent and the result suggests that enol aldehyde formation is greatly favored in an aprotic environment.
authors.affiliation: Global Quality Services - Analytical Sciences, Schering-Plough Corporation, 1011 Morris Avenue, Union, NJ 07083, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Chen
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Mingxiang
authors.initials: M
authors.lastname: Lin
authors.forename: Gilbert
authors.initials: G
authors.lastname: Tumambac
authors.forename: Abu
authors.initials: A
authors.lastname: Rustum
mesh_terms: D001507:Beclomethasone / Q000737:chemistry*; D001623:Betamethasone / Q000737:chemistry*; D003907:Dexamethasone / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007536:Isomerism; D015394:Molecular Structure
chemical_list: D003907:Dexamethasone; D001623:Betamethasone; D001507:Beclomethasone